The present invention relates to a preventive or therapeutic agent for cerebral stroke comprising an interleukin-8 (IL-8)-binding-inhibition agent as an active ingredient. The present invention also relates to a preventive or therapeutic agent for cerebral edema comprising an IL-8-binding-inhibition agent as an active ingredient. The present invention also relates to a preventive or therapeutic agent for reperfusion injury of cerebral ischemia comprising an IL-8-binding-inhibition agent as an active ingredient. Furthermore, the present. invention relates to a preventive or therapeutic agent for increased cerebral vascular permeability comprising an IL-8-binding-inhibition agent as an active ingredient.
IL-8 is a protein that belongs to the C-X-C chemokine subfamily and was formerly designated as the monocyte-derived neutrophil chemotactic factor, the neutrophil attractant/activation protein-1, the neutrophil activating factor and the like. IL-8 is a factor that activates neutrophils and provide them with a migratory ability, and is produced by inflammatory cytokines such as IL-1xcex2 and TNF-xcex1 (Koch, A. E. et al., J. Investig. Med. (1995) 43, 28-38; Larsen, C. G. et al., Immunology (1989) 68, 31-36), mitogens such as PMA and LPS (Yoshimura, T. et al, Proc. Natl. Acad. Sci. U.S.A. (1987) 84, 9233-9237), and heavy metals such as Cadmium (Horiguchi, H. et al., Lymphokine Cytokine Res. (1993) 12, 421-428) in a variety of cells. It is also known that human umbilical endothelial cells under a low oxygen condition express IL-8 (Karakurum, M. et al., J. Clin. Invest. (1994) 93, 1564-1570).
In order for IL-8 to exhibit its biological activity, it is necessary that IL-8 binds to IL-8 receptor and thereby stimulates the cells that are expressing IL-8 receptors. IL-8 receptors that transmit signals into the cell by binding to IL-8 have already been cloned and the amino acid sequences thereof have been elucidated. Human IL-8 receptors include those referred to as IL-8 receptor A (xcex1 or 2) and those referred to as IL-8 receptor B (xcex2 or 1) (Murphy, P. M. and Tiffany, H. L., Science (1991) 253, 1280-1283; Holmes, W. E. et al., Science (1991) 253, 1278-1280). Both receptors are thought to have a structure that penetrates the cell membrane seven times, and both are associated with GTP-binding proteins in the cytoplasmic domain (Horuk, R., Trends Pharmacol. Sci. (1994) 15, 159-165), and transmit IL-8 signals into the cell. Therefore, inhibition of binding,between IL-8 and IL-8 receptor enables the inhibition of biological activity of IL-8.
The IL-8 binding-inhibition agents so far known include the following substances. As anti-IL-8 antibodies, there are known WS-4 antibody (Ko, Y. et al., J. Immunol. Methods (1992) 149, 227-235), 14E4, 46E5 (Sticherling, M. et al., J. Immunol. (1989) 143, 1628-1634), and human antibody (International Patent Application WO 96/33735), and besides, a polysaccharide (International Patent Application WO 94/18989), a chemical synthetic compound (Sola, F. et al., Invasion Metastasis (1995) 15, 222-231), a peptide fragment (Hayashi, S. et al., J. Immunol. (1995) 154, 814-824), and the like.
With respect to the involvement of IL-8 in reperfusion injury of ischemia, the following findings have been obtained. It has already been reported that in the experimental animal model of reperfusion injury of pulmonary ischemia, the administration of anti-IL-8 antibody at reperfusion following 2 hours of pulmonary ischemia inhibited damages to lung tissues (Sekido, N. et al., Nature (1993) 365, 654-657). On the other hand, though the expression of IL-8 in myocardial tissues after reperfusion has been reported (Ivey, C. L. et al., J. Clin. Invest. (1995) 95, 2720-2728; Kukielka, G. L. et al. J. Clin. Invest. (1995) 95, 89-103), the effect of neutralizing IL-8 is unknown. Rather, it is reported that by administering before reperfusion IL-8 per se that is elevated by reperfusion, the formation of the focus of myocardial infarction is inhibited (Lefer, A. M. et al., Br. J. Pharmacol. (1991) 103, 1153-1159). However, it is unknown whether IL-8 is involved in cerebral infarction, cerebral edema, reperfusion injury of cerebral ischemia, and increased cerebral vascular permeability.
From its mechanism of onset, cerebral apoplexy is classified into the occlusive cerebral vascular injury and the hemorrhagic cerebral vascular injury. The occlusive cerebral vascular injury includes cerebral infarction, and the hemorrhagic cerebral vascular injury includes subarachnoid hemorrhage and cerebral hemorrhage. Cerebral infarction is a condition in which occlusion or decreased perfusion pressure in cerebral and carotid arteries occurred for any reason, thereby causing ischemic necrosis in the brain tissue, and the disease is further divided broadly into the thrombotic, embolic and the hemodynamic infarctions.
The condition in which a sclerotic lesion in the brain arteries combined with increased blood viscosity or decreased perfusion pressure caused anterior occlusion leading to ischemic necrosis is referred to as cerebral thrombosis, the condition in which embolism was formed in the brain artery by intracardiac thrombus or the occasionally ablated mural thrombus of artery is referred to as cerebral embolism, and when the stenosis or occlusion of the cranial and intracranial arteries causes decreased blood flow into the peripheral brain tissues leading to infarction, it is referred to as hemodynamic infarction (Toshio Matobe and Teruo Omae, ed., xe2x80x9cNoukekkan Shougai (Cerebral Vascular Injuries),xe2x80x9d Life Science Shuppan, 54-55, 1992; Hiroo Imura ed., xe2x80x9cNoukekkan Shougai (Cerebral Vascular Injuries),xe2x80x9d in Saishin Naikagaku Taikei (Institution of the Latest Internal Medicine), vol. 66, Nakayama Shoten, 28, 1996).
In the brain tissue that has fallen into ischemia because of cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage, the formation of ischemic cerebral edema may be observed. In the case of cerebral infarction, cerebral edema appears a few hours after the onset and persists up to one week after the onset. Thereafter cerebral edema gradually decreases and, depending on the scope of the infarct, becomes fixed as the lesion of the infarct during the one to three months after the onset of the disease. In cerebral hemorrhage, cerebral edema becomes manifest in the periphery of hematoma generally about 6 hours after the onset of the disease due to impaired blood flow at the peripheral territory of the disrupted arteries and impaired circulation and tissue necrosis arising from compression by hematoma (Hiroo Imura ed., xe2x80x9cNoukekkan Shougai (Cerebral Vascular Injuries),xe2x80x9d in Saishin Naikagaku Taikei (Institution of the Latest Internal Medicine), vol. 66, Nakayama Shoten, 289, 1996).
In the case of subarachnoid hemorrhage, delayed spasm is observed 3 days to 3 weeks after hemorrhage, and the spasm is associated with decreased cerebral perfusion pressure which causes delayed cerebral ischemia. Those unresponsive to treatment develop into cerebral infarction, which in severe cases cause ischemic cerebral edema (Hiroo Imura ed., xe2x80x9cNoukekkan Shougai (Cerebral Vascular Injuries),xe2x80x9d in Saishin Naikagaku Taikei (Institution of the Latest Internal Medicine), vol. 66, Nakayama Shoten, 163, 1996). Cerebral edema causes an increase in the volume of the brain. Since the brain is covered with the hard cranium, cerebral edema, when it surpasses a certain degree, may cause a sudden rise in tissue pressure and intracranial pressure, which eventually aggravates brain disorders and determines the future scope of the lesion of the infarct (Kenji Inamura and Akiro Kaku, Nippon Rinsho Vol. 51, xe2x80x9cCT, MRI Jidaino Nosocchu Gaku, Jokan (Stroke in the Age of CT and MRI, the first volume),xe2x80x9d Nippon Rinsho (Japan Clinic), 231-239, 1993). When a part of the brain falls into infarction, the functions carried by the region such as recognition, consciousness, sensation, and memory are lost.
Cerebral edema often occurs in head injuries especially brain contusion, acute subdural hematoma, and acute intracranial hematoma. Cerebral edema serves as an enlarged intracranial lesion with a result that local neurological symptoms become manifest, and intracranial swelling and increased pressure lead to the formation of transtentorial herniation and transforaminal herniation in the brain tissue, which becomes fatal (The Japanese edition of Merck Manual, Vol. 1, Medical Book Service, 1405-1406, 1994).
Furthermore, a surgical operation such as craniotomy may be practiced for the purpose of treating head injury, cerebral hemorrhage, subarachnoid hemorrhage, cerebral tumor, and the like. In order to avoid secondary bleeding in these occasions, the blood vessels whose territory is to be treated may be temporarily occluded with an arterial clip etc. to partially block the cerebral blood flow. In such cases, blood flow is resumed after the completion of the desired surgery, when reperfusion injury of ischemia may occur. Furthermore, among the surgical processes for treatment of cerebral infarction is anastomosis between the superficial temporal artery and the middle cerebral artery. In such cases as well, anastomosis is performed under temporal hemostasis, and blood flow is resumed after the desired surgery, when reperfusion injury of ischemia may occur.
As hereinabove described, the prevention and treatment of cerebral stroke and cerebral edema that affects the prognosis of life and quality of life of the patient is a clinically very important challenge. At present anti platelet agents and agents for improving cerebral circulation metabolism are being administered for treatment of cerebral infarction. Although some anti-platelet agents are effective for treatment of the acute phase of cerebral thrombosis, they are contraindicated for patients with cerebral hemorrhage or cerebral infarction who exhibit similar symptoms, since they accelerate hemorrhagic cerebral infarction, and thereby careful diagnosis of the disease type is required before use (Yukihito Shinohara, xe2x80x9cmedicina,xe2x80x9d Igaku Shoin, Vol. 32, No. 11, 2217-2219, 1995).
Agents for improving cerebral circulation metabolism are drugs that are administered during the chronic phase at one month after an attack of cerebral infarction and after, and are considered to be undesirable for use during the acute phase (Masakuni Kameyama ed., xe2x80x9cNosocchu Chiryo Manual (Manual of Cerebral Stroke Treatment),xe2x80x9d Igaku Shoin, 172-173, 1991). In recent years, for the purpose of resuming blood flow in areas that have not yet fallen into irreversible cell death during the super acute phase after the onset, thrombolytic therapy, bypass surgery, thromboendarterectorny, embolectomy and the like have been performed. Unlike myocardial infarction, however, the resumption of blood flow after an irreversible damage was imparted to the brain tissue may cause reperfusion injury of ischemia such as increases in hemorrhagic infarction and cerebral edema in which tissue damage is aggravated, providing a new problem to be solved (Yasushi Okada, xe2x80x9cSinkei Kenkyuno Shinpo (Advances in Neurological Studies),xe2x80x9d Igaku Shoin, Vol. 40, No. 4, 655-665, 1996; Akira Takahashi, xe2x80x9cmedicina,xe2x80x9d Igaku Shoin, Vol. 32, No. 11, 2261-2263, 1995).
As hereinabove stated, the drugs currently used during the acute phase of cerebral infarction may have side effects such as hemorrhagic infarction and reperfusion injury of ischemia, or may have limitations in the indicated pathological conditions and the timing of administration when the therapeutic effects can be expected, and therefore are not satisfactory.
On the other hand, though treatment of cerebral edema relies on the administration of a hypertonic solution, a steroid, or others in combination with hyperpnea and cerebrospinal fluid drainage, its effects are in most cases transient, and its eventual effects of treatment are not very promising (Masakuni Kameyama ed., xe2x80x9cNosocchu Chiryo Manual (Manual of Cerebral Stroke Treatment),xe2x80x9d Igaku Shoin, 34-36, 1991).
It is therefore desired to develop a drug having a completely new mechanism different from the conventional etiology as a method of preventing or treating cerebral infarction, cerebral edema, reperfusion injury of cerebral ischemia during reperfusion therapy, or reperfusion injury of cerebral ischemia associated with reperfusion after transient blocking of cerebral blood flow during surgery.
It is an object of the present invention to provide a new preventive or therapeutic agent for such diseases.
Disclosure of the Invention
As a result of an intensive study to provide such a preventive or therapeutic agent, the applicants have found that an IL-8 binding-inhibition agent can attain the desired object and thereby have completed the present invention.
Thus, the present invention provides a preventive or therapeutic agent for cerebral stroke comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral infarction comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral thrombosis comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral embolism comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for hemodynamic infarction comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for, hemorrhagic cerebrovascular disorders comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral hemorrhage comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for subarachnoid hemorrhage comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral edema comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for ischemic cerebral edema comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral edema associated with head injuries comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for reperfusion injury of cerebral ischemia comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for reperfusion injury of cerebral ischemia associated with reperfusion after transient blocking of cerebral blood flow during surgery comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for reperfusion injury of cerebral ischemia associated with thrombolytic therapy comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for increased vascular permeability comprising an IL-8 binding-inhibition agent as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral stroke comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral infarction comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral thrombosis comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral embolism comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for hemodynamic infarction comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for hemorrhagic cerebrovascular disorders comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral hemorrhage comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for subarachnoid hemorrhage comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral edema comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for ischemic cerebral edema comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral edema associated with head injuries comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for reperfusion injury of cerebral ischemia comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for reperfusion injury of cerebral ischemia associated with reperfusion after transient blocking of cerebral blood flow during surgery comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for reperfusion injury of cerebral ischemia associated with thrombolytic therapy comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for increased vascular permeability comprising anti-IL-8 antibody as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral infarction, cerebral edema, reperfusion injury of cerebral ischemia, and increased cerebral vascular permeability comprising a monoclonal antibody against IL-8 as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral infarction, cerebral edema, reperfusion injury of cerebral ischemia,.and increased cerebral vascular permeability comprising an antibody against mammalian IL-8 as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral infarction, cerebral edema, reperfusion injury of cerebral ischemia, and increased cerebral vascular permeability comprising an antibody against human-IL-8 as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral infarction, cerebral edema, reperfusion injury of cerebral ischemia, and increased cerebral vascular permeability comprising WS-4 antibody against IL-8 as an active ingredient.
The present invention also provides a preventive or therapeutic agent for cerebral infarction, cerebral edema, reperfusion injury of cerebral ischemia, and increased cerebral vascular permeability comprising a humanized or chimeric antibody against IL-8 as an active ingredient.
The present invention further provides a preventive or therapeutic agent for cerebral infarction, cerebral edema, reperfusion injury of cerebral ischemia, and increased cerebral vascular permeability comprising humanized WS-4 antibody against IL-8 as an active ingredient.